These studies are designed to investigate the biosynthesis, utilization and metabolism of heme, and the regulation of hemoprotein function in mammalian tissues. Particular emphasis will be placed upon understanding factors affecting the regulation of heme and hemoprotein levels at different stages of development and during chronic disease processes. Elucidation of alterations in heme biosynthetic parameters incurred by exposure to hematotoxic environmental agents will be of special interest. Substances under current investigation include various trace metals and the chlorinated hydrocarbon, TCDD. A specific mechanism for the role of heme in the regulation of cytochrome oxidase in fetal liver has been proposed. Current studies suggest that heme may also limit the synthesis of microsomal cytochrome P-450 in mammalian liver under circumstances wherein heme biosynthesis is chronically impaired. A model system in which hepatic heme biosynthesis and mixed function oxidase activity are chronically impaired as result of exposure to the hepatocarcinogen ethionine is being developed in order to assess the effects of impaired heme biosynthesis on microsomal hemoprotein function resulting from exposure to a variety of environmental hematotoxic agents. BIBLIOGRAPHIC REFERENCES: Fowler, B.A. and Woods, J.S.: The transplacental toxicity of methyl mercury to fetal rat liver mitochondria: Morphometric and biochemical studies. Lab Invest. 36: 122-130, 1977. Woods, J. S.: Heme regulation of cytochrome oxidase synthesis in fetal rat liver. Molec. Pharmacol. 13: 50-59, 1977.